KCNH2 Variant A57P

Summary of observed carriers, functional annotations, and structural context for KCNH2 A57P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

15%

90% CI: 6.2% – 45.6%

2/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A57P has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 96% of WT with a standard error of 13%. In our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong.

Variant features alone are equivalent to phenotyping 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-0.505 0.001 4 0.688 79

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. BLAST-PSSM reflects evolutionary conservation; more negative values indicate rarer substitutions. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source Year Carriers Unaffected LQT2 Other Disease
24103226 2014 1 0 1 Seizures
Literature, cohort, and gnomAD – 1 0 1 –
Variant features alone – 10 9 1 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD. Note that some residues appear multiple times at different distances since the functional KV11.1 channel (protein product of KCNH2/hERG) is a homotetramer and occasionally the same residue from multiple subunits is present within the 15Å window.

Previously observed variants near A57P.
Neighbour residue Distance (Å) Observed variants
57 0 A57P,
58 4 E58K, E58D, E58D,
55 5 S55L,
859 5 T859M, T859R,
60 6 M60T,
59 6
56 6 R56Q,
857 6 E857X,
858 7 I858V, I858T,
61 8 Q61R,
860 8
62 8 R62Q,
44 9 C44F, C44X, C44W,
54 9 Y54N, Y54X,
861 9 N861H, N861I,
804 10
41 10 V41A,
49 10 C49R, C49G,
803 11 D803Y, D803X,
856 11
53 11 G53S, G53R,
799 11 L799sp,
68 12 F68L, F68V, F68L, F68L,
42 12 I42N,
806 12 G806R, G806R,
797 12 A797T,
43 12 Y43D, Y43C,
48 12
52 12 C52W,
805 12 F805S, F805C,
862 12 L862P,
101 13 K101E,
40 13
808 13
855 13 S855R, S855R, S855R,
798 13 I798fsX,
63 13 P63H,
796 13 V796L, V796L, V796Del,
741 13 K741R,
45 13 N45D, N45K, N45K,
46 13 D46Y, D46E, D46E,
854 13
800 13
802 14
807 14 E807X,
30 14 I30Del, I30T,
789 14
66 14 C66R, C66G, C66Y,
69 15 L69Del, L69P,
31 15 I31S
782 15 I782fsX, I782N,
853 15 W853X,
47 15 G47C, G47V,